# The ion channel TRPA1 is required for suppression of inflammation in sepsis

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2021 · $335,000

## Abstract

Abstract
Sepsis represents a huge unmet medical need: it annually afflicts nearly 1 million individuals in
the United States, killing >200,000. The pathophysiology of sepsis and other inflammatory
disorders is mediated by dysregulated innate immune responses and abnormally elevated
cytokine levels. The inflammatory reflex consists of a neural-immune circuit composed of sensory
(afferent) and motor (efferent) vagal neurons that regulate cytokine production in the spleen. The
molecular mechanisms of the motor arc are well defined, but considerably less is known about
the sensory arc of the inflammatory reflex. In the motor arc, action potentials arise in the vagus
nerve, travel in the splenic nerve, and culminate on lymphocytes that are activated to produce
acetylcholine, a neurotransmitter molecule that inhibits cytokine production via signaling through
7 nicotinic acetylcholine receptor (7nAChR), expressed on macrophages and monocytes.
Using novel electrophysiological recording and decoding methods, we recently identified
cytokine-specific sensory neural signals in the vagus nerve. These studies revealed a novel role
for an ion channel, transient receptor potential ankyrin-repeat 1 (TRPA1), in the afferent vagus
nerve response to IL-1, and selective activation of TRPA1 afferent fibers in the vagus nerve,
which also suppresses TNF levels in endotoxemia. Here, we hypothesize that TRPA1 plays an
essential role in mediating interleukin-1 (IL-1)-induced vagus nerve activation, and selective
stimulation of TRPA1 expressing vagus nerve fibers will improve survival and pathophysiology in
sepsis. This hypothesis will be addressed in the following two Specific Aims: Specific Aim 1.
Elucidate the role of TRPA1 in mediating IL-1-induced activation of the inflammatory reflex.
Specific Aim 2. Assess the dynamics of vagus nerve activity and evaluate the effects of selective
TRPA1 stimulation on survival and pathophysiology in sepsis. We propose to utilize a novel
approach that integrates experiments assessing direct binding and colocalization of TRPA1 with
IL-1Rs on the sensory neurons, analysis of action potential generation in neurons, and evaluating
the role of TRPA1-dependent pathophysiological effects in animals subjected to sepsis. This
significant new research will provide novel and impactful data for an innovative molecular
mechanism of the afferent (sensory) arc of the inflammatory reflex and its role in sepsis. This data
will pave the way to develop novel therapeutic modalities for the prevention and treatment of
sepsis/septic shock.

## Key facts

- **NIH application ID:** 10102258
- **Project number:** 5R01GM132672-03
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Sangeeta S. Chavan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,000
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102258

## Citation

> US National Institutes of Health, RePORTER application 10102258, The ion channel TRPA1 is required for suppression of inflammation in sepsis (5R01GM132672-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102258. Licensed CC0.

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